Massive Bioaccumulation and Self‐Assembly of Phenazine Compounds in Live Cells

Advanced Science

Kyoung Ah Min²  Walajapet G. Rajeswaran⁵  Rudolf Oldenbourg⁴  Grant Harris⁴  Rahul K. Keswani²  Mason Chiang²  Phillip Rzeczycki²  Arjang Talattof²  Mahwish Hafeez²  Richard W. Horobin¹  Scott D. Larsen⁵  Kathleen A. Stringer³ 

[1] School of Life Sciences, The University of Glasgow, Glasgow, Scotland, UK;Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, MI, USA;Department of Clinical, Social and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, MI, USA;Marine Biological Laboratories, Woods Hole, MA, USA;Department of Medicinal Chemistry, University of Michigan College of Pharmacy, Ann Arbor, MI, USA

关键词: aggregation;    biocrystals;    chromophores;    clofazimine;    medicinal chemistry;   

DOI  :  10.1002/advs.201500025

来源: Wiley

【 摘 要 】

Abstract

Clofazimine is an orally administered drug that massively bioaccumulates in macrophages, forming membrane-bound intracellular structures possessing nanoscale supramolecular features. Here, a library of phenazine compounds derived from clofazimine is synthesized and tested for ability to accumulate and form ordered molecular aggregates inside cells. Regardless of chemical structure or physicochemical properties, bioaccumulation is consistently greater in macrophages than in epithelial cells. Microscopically, some self-assembled structures exhibit a pronounced, diattenuation anisotropy signal, evident by the differential absorption of linearly polarized light, at the peak absorbance wavelength of the phenazine core. The measured anisotropy is well above the background anisotropy of endogenous cellular components, reflecting the self-assembly of condensed, insoluble complexes of ordered phenazine molecules. Chemical variations introduced at the R-imino position of the phenazine core lead to idiosyncratic effects on the compounds' bioaccumulation behavior as well as on the morphology and organization of the resulting intracellular structures. Beyond clofazimine, these results demonstrate how the self-assembly of membrane permeant, orally bioavailable small molecule building blocks can endow cells with unnatural structural elements possessing chemical, physical, and functional characteristics unlike those of other natural cellular components.

【 授权许可】

CC BY   
© 2015 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.